Noninvasive mechanical ventilation assistance in amyotrophic lateral sclerosis: a systematic review

ABSTRACT BACKGROUND: Respiratory failure is the most common cause of death in patients with amyotrophic lateral sclerosis (ALS), and morbidity is related to poor quality of life (QOL). Non-invasive ventilation (NIV) may be associated with prolonged survival and QOL in patients with ALS. OBJECTIVES: To assess whether NIV is effective and safe for patients with ALS in terms of survival and QOL, alerting the health system. DESIGN AND SETTING: Systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting standards using population, intervention, comparison, and outcome strategies. METHODS: The Cochrane Library, CENTRAL, MEDLINE, LILACS, EMBASE, and CRD databases were searched based on the eligibility criteria for all types of studies on NIV use in patients with ALS published up to January 2022. Data were extracted from the included studies, and the findings were presented using a narrative synthesis. RESULTS: Of the 120 papers identified, only 14 were related to systematic reviews. After thorough reading, only one meta-analysis was considered eligible. In the second stage, 248 studies were included; however, only one systematic review was included. The results demonstrated that NIV provided relief from the symptoms of chronic hypoventilation, increased survival, and improved QOL compared to standard care. These results varied according to clinical phenotype. CONCLUSIONS: NIV in patients with ALS improves the outcome and can delay the indication for tracheostomy, reducing expenditure on hospitalization and occupancy of intensive care unit beds. SYSTEMATIC REVIEW REGISTRATION: PROSPERO database: CRD42021279910 — https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=279910.


Design and setting
The review protocol was registered with the International Prospective Register of Systematic Reviews database (www.crd. york.ac.uk/prospero/; registration number CRD42021279910) and was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting standards 9 using the PICO strategy for research question construction and evidence search. 8,10 Research strategy presents the search strategy adopted. Systematic reviews of randomized clinical trials with or without meta-analyses, and individual randomized clinical trials on the use of NIV in patients with ALS were sought. Systematic reviews of good methodological quality with meta-analyses were prioritized because of their higher levels of evidence. If no such reviews existed, a search for individual studies was planned.
The search strategy was created using the PICO strategy. 10 The patients (P) used in the search strategy were those with ALS and an indication for ventilatory assistance. A rapid initial investigation was conducted to create an intervention section for the search strategy. Intervention (I) was the indication for NIV. Comparison (C) was defined as a standard treatment that did not involve NIV or other comparators. Outcomes (O) are related to quality of care, including survival, quality of life, and other clinical outcomes.
For this review, the following studies were excluded: duplicates, non-comparative studies, comparative studies with a retrospective design, and studies published only in an abstract format or the like, without complete data that would make it possible to assess the methods.
The two reviewers searched the databases using a previously defined strategy. Based on these criteria, they selected studies for inclusion in this review. In the event of a lack of consensus between the two reviewers, a third reviewer was consulted regarding eligibility and was responsible for making the final decision. The included studies were evaluated for level of evidence using the Oxford Centre of Evidence-Based Medicine Levels of Evidence. 11 This review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations 9 and is presented using narrative synthesis.

Search results
The articles were selected in stages. First, systematic reviews with or without meta-analyses were selected, given their higher quality regarding the hierarchy of evidence. Through a search of the databases for systematic reviews, 120 non-duplicated titles were identified. Two reviewers applied the eligibility criteria and initially selected 14 articles for full reading that were potentially related to systematic reviews. Among these, one systematic review and meta-analysis by the Cochrane Collaboration was considered eligible (Figure 1). Two systematic reviews with adequate search and selection methods were excluded after reading them completely because they included non-comparative cohort studies with prospective or retrospective designs.
In the second stage, the individual studies were screened and selected according to the strategies described above. Of the 248 registered articles, two were selected for full reading. Only two were selected and included in this review (Figure 2). Initially, two RCTs involving 54 participants with ALS receiving NIV were included. One of these studies (n = 13) compared the early and late use of NIV and presented incomplete data. Missing  Full-text articles assessed for eligibility (n = 14)

A systematic review with meta-analysis produced through the Cochrane Collaboration
Records excluded (do not meet inclusion criteriaor are unrelated to the topic of review) (n = 106) Full-text articles excluded (did not meet inclusion criteria) (n = 13) Total studies included (n = 1)      Adverse events related to NIV or the comparators were not evaluated or reported; thus, no information was obtained from the RCT.

Comparative observational study
Berlowitz et al. 12  Univariate comparisons were made between baseline characteristics and survival analyses, with adjustments for age at disease onset, sex, use of riluzol, and use of percutaneous endoscopic gastrostomy. In addition, a mixed-model analysis was used to assess the rate of decline in respiratory function (forced vital capacity, forced expiratory volume in 1 second, maximal inspiratory pressure, maximal expiratory pressure, and sniff nasal inspiratory pressure) before and after initiation of NIV. This model enabled analysis involving "before and after" comparison among patients using NIV, in which the main parameter of interest was the interaction between the use of NIV and the time elapsed since the start of NIV use. As this analysis did not make a comparison with any group of patients who did not receive NIV, these results were not considered eligible and were not included as an outcome of interest in the present review.

DISCUSSION
It has been consistently demonstrated that NIV therapy relieves the symptoms of chronic hypoventilation and increases survival. 7 Two studies evaluated the effects of NIV among patients with ALS and respiratory insufficiency with an indication for ventilatory support: a Cochrane systematic review and a retrospective analysis of a prospective cohort conducted in Australia. This systematic review included only a single eligible RCT with 41 participants; however, the methodological quality was considered adequate (low risk of bias).
As shown by the available evidence, patient survival is increased through the use of NIV, including in specific subgroups that are defined according to bulbar function 5 and the ALS phenotype. 12 In addition, the Cochrane systematic review conducted by Radunovic et al. 5 demonstrated an improvement in quality-of-life parameters among patients who were treated with NIV for a longer time. The author identified scores > 75%

All participants
Median length of time for which the score remained more than 75% above the baseline was 99 days

All participants
Median length of time for which the score remained more than 75% above the baseline was 69 days longer (45 to 667)

(one study) Low
Participants with better bulbar function Median length of time for which the score remained more than 75% above the baseline was 4 days

Participants with better bulbar function
Median length of time for which the score remained more than 75% above the baseline was 195 days longer (P = 0.001; CI not reported) Participants with poor bulbar function Median length of time for which the score remained more than 75% above the baseline was 164 days Participants with poor bulbar function Median length of time for which the score remained more than 75% above the baseline was 37 days shorter (P = 0.64; CI not reported)

All participants
Median length of time for which the score remained more than 75% above the baseline was 81 days

All participants
Median length of time for which the score remained more than 75% above the baseline was 69 days longer (P = 0.004)

(one study) Low
Participants with better bulbar function Median length of time for which the score remained more than 75% above the baseline was 4 days

Participants with better bulbar function
Median length of time for which the score remained more than 75% above the baseline was 175 days longer (P < 0.001) Participants with poor bulbar function Median length of time for which the score remained more than 75% above the baseline was 132 days Participants with poor bulbar function Median length of time for which the score remained more than 75% above the baseline was 18 days longer (P = 0.88)

Sleep Apnea Quality of Life Index (SAQLI)
All participants Median length of time for which the score remained more than 75% above the baseline was 99 days

All participants
Median length of time for which the score remained more than 75% above the baseline was 74 days longer (P = 0.031)

(one study) Low
Participants with better bulbar function Median length of time for which the score remained more than 75% above the baseline was 4 days

Participants with better bulbar function
Median length of time for which the score remained more than 75% above the baseline was 195 days longer (P < 0.001) Participants with poor bulbar function Median length of time for which the score remained more than 75% above the baseline was 132 days Participants with poor bulbar function Median length of time for which the score remained more than 75% above the baseline was 29 days shorter (P = 0.77)

CONCLUSION
The benefits of NIV in patients with ALS have been demonstrated over the last two decades. It improves the outcome and can delay the indication for tracheostomy, reduce expenditure on hospitalization, and increase the occupancy of intensive care unit beds.
The information presented in this review can be used as a source of knowledge for physicians and researchers to aid public policy strategies.